Neuronavigated aiTBS for TRD

Inclusion criteria

• Age: 18 to 65 years at the time of consent
• Diagnosis: Current major depressive episode (MDE) in the context of unipolar major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), confirmed by clinical psychiatric interview
• Treatment Resistance: Documented failure to respond to at least two adequate antidepressant trials on the Antidepressant Treatment History Form-Short Form (ATHF-SF). An adequate trial is defined as:

• Antidepressant medication at the maximum tolerated dose for at least 6 weeks, OR
• Evidence-based psychotherapy consisting of at least 12 sessions
• Depression Severity: Montgomery-Åsberg Depression Rating Scale (MADRS) score >19 at screening, indicating moderate to severe depression
• Medication Stability: No changes in antidepressant medication type or dose for at least 6 weeks prior to randomization. Stable doses of permitted medications must be maintained throughout the trial
• Informed Consent: Demonstrated capacity to provide written informed consent and comply with study procedures
• Availability: Ability to attend treatment sessions for 15 consecutive workdays (approximately 90 minutes per day) and complete assessments including 4-hour evaluations at baseline and endpoint

Exclusion criteria

Psychiatric Exclusions:

• Any psychiatric disorder other than MDD and comorbid anxiety disorders, including but not limited to:

(i) Bipolar disorder (Type I or II) (ii) Schizophrenia spectrum or other psychotic disorders (iii) Post-traumatic stress disorder (PTSD) (iv) Attention-deficit/hyperactivity disorder (ADHD) (v) Autism spectrum disorder (ASD) (vi) Obsessive-compulsive disorder (OCD) (vii) Current DSM-5 substance-use disorder (abuse or dependence) within the past 6 months, except nicotine dependence

• Personality disorder confirmed on clinical interview by an experienced study psychiatrist
• Severe suicidal ideation with structured plan (HDRS-17 item 3 score >2) or as determined by the evaluating psychiatrist
• Depressive symptoms better explained by another psychiatric condition, a medical condition, substance use, or use of medications

Medical and Neurological Exclusions:

• Any neurological disorder including but not limited to:

(i) History of seizure disorder or epilepsy (ii) Family history of epilepsy (first-degree relatives) (iii) Significant head trauma with loss of consciousness >5 minutes (iv) Stroke or transient ischemic attack (v) Neurodegenerative disorders (e.g., Parkinson's disease, multiple sclerosis, dementia) (vi) Brain tumor or intracranial mass lesion

• Unstable medical condition, defined as any condition requiring acute medical intervention or hospitalization within the past 3 months, or any condition that in the investigator's judgment could affect participant safety or study outcomes

Contraindications to TMS/MRI:

• Presence of ferromagnetic material in or near the head, including:

(i) Intracranial implants (e.g., aneurysm clips, shunts, stimulators) (ii) Cochlear implants or hearing aids (iii) Metallic facial tattoos or permanent makeup (iv) Other implanted medical devices deemed unsafe for MRI/TMS

• Inability to tolerate MRI scanning due to claustrophobia or other reasons

Medication Exclusions:

Current use of medications known to significantly alter cortical excitability:

• Anticonvulsants (including those used for mood stabilization)
• Psychostimulants
• Lithium
• Benzodiazepines exceeding 10mg diazepam-equivalent daily dose

Prior Treatment Exclusions:

• Electroconvulsive therapy (ECT) (≥ 6 sessions) in the current depressive episode
• Ketamine or esketamine treatment (≥ 6 sessions) in the current depressive episode
• Use of rTMS/iTBS (≥ 15 sessions) during the current depressive episode
• Vagus nerve stimulation (VNS) or deep brain stimulation (DBS) implantation

Psychotherapy:

• Concurrent evidence-based psychotherapy is permitted if initiated >4 weeks prior to enrollment and maintained at stable frequency throughout the tria

Other reasons:

• Unable to adhere to the study visit schedule
• Planning to relocate outside the study catchment area during the trial period
• No reliable transportation to attend study visits
• Current participation in another research study
• Current pregnancy (confirmed by in interview and clinical evaluation and, if deemed necessary, urine pregnancy test at screening)
• Currently breastfeeding